Process for the alkoxycarbonylation of alcohols

ABSTRACT

The invention relates to a process comprising the following process steps:
     a) introducing a first alcohol, the first alcohol having 2 to 30 carbon atoms;   b) adding a phosphine ligand and a compound which comprises Pd, or adding a complex comprising Pd and a phosphine ligand;   c) adding a second alcohol;   d) supplying CO;   e) heating the reaction mixture, the first alcohol reacting with CO and the second alcohol to form an ester;
 
where the phosphine ligand is a compound of formula (I)
   

     
       
         
         
             
             
         
       
     
     where
     m and n are each independently 0 or 1;   R 1 , R 2 , R 3 , R 4  are each independently selected from —(C 1 -C 12 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —(C 6 -C 20 )-aryl, —(C 3 -C 20 )-heteroaryl;   at least one of the R 1 , R 2 , R 3 , R 4  radicals is a —(C 3 -C 20 )-heteroaryl radical;   and   R 1 , R 2 , R 3 , R 4 , if they are —(C 1 -C 12 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —(C 6 -C 20 )-aryl or —(C 3 -C 20 )-heteroaryl,   may each independently be substituted by one or more substituents selected from —(C 1 -C 12 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —O—(C 1 -C 12 )-alkyl, —O—(C 1 -C 12 )-alkyl-(C 6 -C 20 )-aryl, —O—(C 3 -C 12 )-alkyl, —S—(C 1 -C 12 )-alkyl, —S—(C 3 -C 12 )-cycloalkyl, —COO—(C 1 -C 12 )-alkyl, —COO—(C 3 -C 12 )-cycloalkyl, —CONH—(C 1 -C 12 )-alkyl, —CONH—(C 3 -C 12 )-cycloalkyl, —CO—(C 1 -C 12 )-alkyl, —CO—(C 3 -C 12 )-cycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , —(C 6 -C 20 )-aryl, —(C 6 -C 20 )-aryl-(C 1 -C 12 )-alkyl, —(C 6 -C 20 )-aryl-O—(C 1 -C 12 )-alkyl, —(C 3 -C 20 )-heteroaryl, —(C 3 -C 20 )-heteroaryl-(C 1 -C 12 )-alkyl, —(C 3 -C 20 )-heteroaryl-O—(C 1 -C 12 )-alkyl, —COON, —OH, —SO 3 H, —NH 2 , halogen.

The present invention relates to a novel process for thealkoxycarbonylation of alcohols.

The alkoxycarbonylation of ethylenically unsaturated compounds is aknown process for preparing esters. This method is used to reactethylenically unsaturated compounds (olefins) with carbon monoxide andalcohols in the presence of a metal-ligand complex to give thecorresponding esters. Typically, the metal used is palladium. Thefollowing scheme shows the general reaction equation of analkoxycarbonylation:

A very good catalytic system for this process was developed byLucite—now Mitsubishi Rayon—and uses a ligand based on1,2-bis(di-tert-butylphosphinomethyl)benzene (DTBPMB) (W. Clegg, G. R.Eastham, M. R. J. Elsegood, R. P. Tooze, X. L. Wang, K. Whiston, Chem.Commun. 1999, 1877-1878).

The possibility of using compounds other than ethylenically unsaturatedcompounds and reacting them with alcohols and CO to give thecorresponding esters, in the form of an alkoxycarbonylation reaction, ishitherto unknown.

Against this background, the problem addressed by the present inventionis that of providing an alkoxycarbonylation process for the preparationof esters, which uses raw materials other than ethylenically unsaturatedcompounds as a starting product. Of particular interest here is the useof alcohols as a starting product for the alkoxycarbonylation.

It has surprisingly emerged that this problem is solved by analkoxycarbonylation process wherein particular benzene-based diphosphineligands are used, in which at least one phosphine group is substitutedby a heteroaryl radical. The process of the invention is notable forhigh yields, based on the alcohols used as reactants.

The invention therefore relates to a process comprising the followingprocess steps:

-   -   a) introducing a first alcohol, the first alcohol having 2 to 30        carbon atoms;    -   b) adding a phosphine ligand and a compound which comprises Pd,        or adding a complex comprising Pd and a phosphine ligand;    -   c) adding a second alcohol;    -   d) supplying CO;    -   e) heating the reaction mixture, the first alcohol reacting with        CO and the second alcohol to form an ester;

where the phosphine ligand is a compound of formula (I)

where

m and n are each independently 0 or 1;

R¹, R², R³, R⁴ are each independently selected from —(C1-C₁₂)-alkyl,—(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl, —(C₆-C₂₀)-aryl,—(C₃-C₂₀)-heteroaryl;

at least one of the R¹, R², R³, R⁴ radicals is a —(C₃-C₂₀)-heteroarylradical;

and

R¹, R², R³, R⁴, if they are —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₃-C₁₂)-heterocycloalkyl, —(C₆-C₂₀)-aryl or —(C₃-C₂₀)-heteroaryl,

may each independently be substituted by one or more substituentsselected from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₃-C₁₂)-heterocycloalkyl, —O—(C₁-C₁₂)-alkyl,—O—(C₁-C₁₂)-alkyl-(C₆-C₂₀)-aryl, —O—(C₃-C₁₂)-cycloalkyl,—S—(C₁-C₁₂)-alkyl, —S—(C₃-C₁₂)-cycloalkyl, —COO—(C₁-C₁₂)-alkyl,—COO—(C₃-C₁₂)-cycloalkyl, —CONH—(C₁-C₁₂)-alkyl,—CONH—(C₃-C₁₂)-cycloalkyl, —CO—(C₁-C₁₂)-alkyl, —CO—(C₃-C₁₂)-cycloalkyl,—N—[(C₁-C₁₂)-alkyl]₂, —(C₆-C₂₀)-aryl, —(C₆-C₂₀)-aryl-(C₁-C₁₂)-alkyl,—(C₆-C₂₀)-aryl-O—(C₁-C₁₂)-alkyl, —(C₃-C₂₀)-heteroaryl,—(C₃-C₂₀)-heteroaryl-(C₁-C₁₂)-alkyl,—(C₃-C₂₀)-heteroaryl-O—(C₁-C₁₂)-alkyl, —COOH, —OH, —SO₃H, —NH₂, halogen.

The first and second alcohols may be identical or different, butpreferably the first and second alcohols are different. In oneembodiment, the first alcohol is a secondary or tertiary alcohol and thesecond alcohol is a primary alcohol.

In this process, process steps a), b), c) and d) can be effected in anydesired sequence. Typically, however, the addition of CO is effectedafter the co-reactants have been initially charged in steps a) to c).Steps d) and e) can be effected simultaneously or successively. Inaddition, CO can also be fed in in two or more steps, in such a waythat, for example, a portion of the CO is first fed in, then the mixtureis heated, and then a further portion of CO is fed in.

In one embodiment, the phosphine ligands according to the invention arecompounds of one of the formulae (II) and (III)

In these formulae, the R¹, R², R³, R⁴ radicals are each as definedabove.

In one particularly preferred embodiment, the phosphine ligand accordingto the invention is a compound of the formula (II) where the radicalsR¹, R², R³ and R⁴ are as defined above.

The expression (C1-C₁₂)-alkyl encompasses straight-chain and branchedalkyl groups having 1 to 12 carbon atoms. These are preferably(C₁-C₈)-alkyl groups, more preferably (C₁-C₆)-alkyl, most preferably(C₁-C₄)-alkyl.

Suitable (C₁-C₁₂)-alkyl groups are especially methyl, ethyl, propyl,isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,2-pentyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl,1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethyipropyl, n-hexyl, 2-hexyl,2-rnethylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl,1,2-dirnethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethlbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethylbutyl, 1-ethyl-2-methylpropyl, n-heptyl,2-heptyl, 3-heptyl, 2-ethylpentyl, 1-propylbutyl, n-octyl, 2-ethylhexyl,2-propylheptyl, nonyl, decyl.

The elucidations relating to the expression (C₁-C₁₂)-alkyl also applyparticularly to the alkyl groups in —O—(C₁-C₁₂)-alkyl,—S—(C₁-C₁₂)-alkyl, —COO—(C₁-C₁₂)-alkyl, —CONH—(C₁-C₁₂)-alkyl,—CO—(C₁-C₁₂)-alkyl and —N—[(C₁-C₁₂)-alkyl]₂.

The expression (C₃-C₁₂)-cycloalkyl encompasses mono-, bi-or tricyclichydrocarbyl groups having 3 to 12 carbon atoms. Preferably, these groupsare (C₅-C₁₂)-cycloalkyl.

The (C₃-C₁₂)-cycloalkyl groups have preferably 3 to 8, more preferably 5or 6, ring atoms,

Suitable (C₃-C₁₂)-cycloalkyl groups are especially cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclododecyl, cyclopentadecyl, norbornyl, adamantyl.

The elucidations relating to the expression (C₃-C₁₂)-cycloalkyl alsoapply particularly to the cycloalkyl groups in —O—(C₃-C₁₂)-cycloalkyl,—S—(C₃-C₁₂)-cycloalkyl, —COO—(C₃-C₁₂)-cycloalkyl,—CONH—(C₃-C₁₂)-cycloalkyl, —CO—(C₃-C₁₂)-cycloalkyl.

The expression (C₃-C₁₂)-heterocycloalkyl encompasses nonaromatic,saturated or partly unsaturated cycloaliphatic groups having 3 to 12carbon atoms, where one or more of the ring carbon atoms are replaced byheteroatoms. The (C₃-C₁₂)-heterocycloalkyl groups have preferably 3 to8, more preferably 5 or 6, ring atoms and are optionally substituted byaliphatic side chains. In the heterocycloalkyl groups, as opposed to thecycloalkyl groups, one or more of the ring carbon atoms are replaced byheteroatoms or heteroatom-containing groups. The heteroatoms or theheteroatom-containing groups are preferably selected from O, S, N,N(═O), C(═O), S(═O). A (C₃-C₁₂)-heterocycloalkyl group in the context ofthis invention is thus also ethylene oxide.

Suitable (C₃-C₁₂)-heterocycloalkyl groups are especiallytetrahydrothiophenyl, tetrahydrofuryl, tetrahydropyranyl and dioxanyl,

The expression (C₆-C₂₀)-aryl encompasses mono-or polycyclic aromatichydrocarbyl radicals having 6 to 20 carbon atoms. These are preferably(C₆-C₁₄)-aryl, more preferably (C₆-C₁₀)-aryl.

Suitable (C₆-C₂₀)-aryl groups are especially phenyl, naphthyl, indenyl,fluorenyl, anthracenyl, phenanthrenyl, naphthacenyl, chrysenyl, pyrenyl,coronenyl. Preferred (C₆-C₂₀)-aryl groups are phenyl, naphthyl andanthracenyl.

The expression (C₃-C₂₀)-heteroaryl encompasses mono-or polycyclicaromatic hydrocarbyl radicals having 3 to 20 carbon atoms, where one ormore of the carbon atoms are replaced by heteroatoms. Preferredheteroatoms are N, O and S. The (C₃-C₂₀)-heteroaryl groups have 3 to 20,preferably 6 to 14 and more preferably 6 to 10 ring atoms.

Suitable (C₃-C₂₀)-heteroaryl groups are especially furyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,pyrazolyl, furazanyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl,pyrazinyl, benzofuranyl, indolyl, isoindolyl, benzimidazolyl, quinolyl,isoquinolyl.

The expression halogen especially encompasses fluorine, chlorine,bromine and iodine. Particular preference is given to fluorine andchlorine.

In one embodiment, the R¹, R², R³, R⁴ radicals, if they are—(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl,—(C₆-C₂₀)-aryl, or —(C₃-C₂₀)-heteroaryl, may each independently besubstituted by one or more substituents selected from —(C₁-C₁₂)-alkyl,—(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl, —O—(C₁-C₁₂)-alkyl,—O—(C₁-C₁₂)-alkyl-(C₆-C₂₀)-aryl, —O—(C₃-C₁₂)-cycloalkyl,—S—(C₁-C₁₂)-alkyl, —S—(C₃-C₁₂)-cycloalkyl, —(C₆-C₂₀)-aryl,—(C₆-C₂₀)-aryl-(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl-O—(C₁-C₁₂)-alkyl,—(C₃-C₂₀)-heteroaryl, —(C₃-C₂₀)-heteroaryl-(C₁-C₁₂)-alkyl,—(C₃-C₂₀)-heteroaryl-O—(C₁-C₁₂)-alkyl, —COOH, —OH, —SO₃H, —NH₂, halogen.

In one embodiment, the R¹, R², R³, R⁴ radicals, if they are—(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl,—(C₆-C₂₀)-aryl, or —(C₃-C₂₀)-heteroaryl, may each independently besubstituted by one or more substituents selected from —(C₁-C₁₂)-alkyl,—(C₃-C₁₂)-cycloalkyl, —O—(C₁-C₁₂)-alkyl,—O—(C₁-C₁₂)-alkyl-(C₆-C₂₀)-aryl, —O—(C₃-C₁₂)-cycloalkyl, —(C₆-C₂₀)-aryl,—(C₆-C₂₀)-aryl-(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl-O—(C₁-C₁₂)-alkyl,—(C₃-C₂₀)-heteroaryl, —(C₃-C₂₀)-heteroaryl-(C₁-C₁₂)-alkyl,—(C₃-C₂₀)-heteroaryl-O—(C₁-C₂)-alkyl.

In one embodiment, the R¹, R², R³, R⁴ radicals, if they are—(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl,—(C₆-C₂₀)-aryl, or —(C₃-C₂₀)-heteroaryl, may each independently besubstituted by one or more substituents selected from —(C₁-C₁₂)-alkyl,—O—(C₁-C₁₂)-alkyl-(C₆-C₂₀)-aryl, —(C₃-C₂₀)-heteroaryl,—(C₃-C₂₀)-heteroaryl-(C₁-C₁₂)-alkyl,—(C₃-C₂₀)-heteroaryl-O—(C₁-C₁₂)-aikyl.

In one embodiment, the R¹, R², R³, R⁴ radicals, if they are—(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₃-C₂)-heterocycloalkyl,—(C₆-C₂₀)-aryl, or —(C₃-C₂₀)-heteroaryl, may each independently besubstituted by one or more substituents selected from —(C₁-C₁₂)-alkyland —(C₃-C₂₀)-heteroaryl.

In one embodiment, the R¹, R², R³, R⁴ radicals are unsubstituted if theyare —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, or—(C₃-C₁₂)-heterocycloalkyl, and may be substituted as described if theyare —(C₆-C₂₀)-aryl, or —(C₃-C₂₀)-heteroaryl.

In one embodiment, the R¹, R², R³, R⁴ radicals are unsubstituted if theyare —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₃-C₂₀)-heterocycloalkyl,—(C₆-C₂₀)-aryl, or —(C₃-C₂₀)-heteroaryl.

In one embodiment, R¹, R², R³, R⁴ are each independently selected from—(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl, —(C₃-C₂₀)-heteroaryl;

where at least one of the R¹, R², R³, R⁴ radicals is a—(C₃-C₂₀)-heteroaryl radical;

and R¹, R², R³, R⁴, if they are —(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl or—(C₃-C₂₀)-heteroaryl, may each independently be substituted by one ormore of the above-described substituents.

In one embodiment, at least two of the R¹, R², R³, R⁴ radicals are a—(C₃-C₂₀)-heteroaryl radical.

In one embodiment, the R¹ and R³ radicals are each a—(C₃-C₂₀)-heteroaryl radical and may each independently be substitutedby one or more of the substituents described above. Preferably, R² andR⁴ are independently selected from —(C₁-C₁₂)-alkyl,—(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl, —(C₆-C₂₀)-aryl, morepreferably from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₆-C₂₀)-aryl,most preferably from —(C₁-C₁₂)-alkyl. R² and R⁴ may independently besubstituted by one or more of the above-described substituents,

In one embodiment, the R¹, R², R³ and R⁴ radicals are a—(C₆-C₂₀)-heteroaryl radical and may each independently be substitutedby one or more of the substituents described above.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are each independently selected from heteroarylradicals having five to ten ring atoms, preferably five or six ringatoms.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are a heteroaryl radical having five ring atoms.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are each independently selected from heteroarylradicals having six to ten ring atoms.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are a heteroaryl radical having six ring atoms.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are selected from furyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,furazanyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl,benzofuranyl, indolyl, isoindolyl, benzimidazolyl, quinolyl,isoquinolyl, where the heteroaryl radicals mentioned may be substitutedas described above.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are selected from furyl, thienyl, pyrrolyl,imidazolyl, pyridyl, pyrimidyl, indolyl, where the heteroaryl radicalsmentioned may be substituted as described above.

In one embodiment, the R¹, R², R³ and R⁴ radicals, if they are aheteroaryl radical, are selected from 2-furyl, 2-thienyl, 2-pyrrolyl,2-imidazolyl, 2-pyridyl, 2-pyrimidyl, 2-indolyl, where the heteroarylradicals mentioned may be substituted as described above.

In one embodiment, the R¹, R², R' and R⁴ radicals, if they are aheteroaryl radical, are selected from 2-furyl, 2-thienyl,N-methyl-2-pyrrolyl, N-phenyl-2-pyrrolyl,N-(2-methoxyphenyl)-2-pyrrolyl, 2-pyrrolyl, N-methyl-2-imidazolyl,2-imidazolyl, 2-pyridyl, 2-pyrimidyl, N-phenyl-2-indolyl, 2-indolyl,where the heteroaryl radicals mentioned have no further substitution.

More preferably, the R^(T), R², R³ and R⁴ radicals, if they are aheteroaryl radical, are pyridyl, especially 2-pyridyl.

In one embodiment, R¹ and R³ are a pyridyl radical, preferably2-pyridyl, and R² and R⁴ are —(C₁-C₁₂)-alkyl, where R¹, R², R³ and R⁴may each be substituted as described above.

In one embodiment, the phosphine ligands are a compound of formula (1):

The alcohols used in step a) as a starting product in the processaccording to the invention comprise 2 to 30 carbon atoms, preferably 3to 22 carbon atoms, more preferably 4 to 12 carbon atoms. They may beprimary, secondary or tertiary alcohols. The alcohols may also comprisearomatic groups.

The alcohol used in step a) is preferably a secondary or tertiaryalcohol.

In one embodiment, the first alcohol used in step a) is a compound ofthe formula (IV)

where R⁵ is selected from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₆-C₂₀)-aryl;

and R⁶ and R⁷ are each independently selected from —H, —(C₁-C₁₂)-alkyl,—(C₃-C₁₂)-cyclo-alkyl, —(C₆-C₂₀)-aryl.

In one preferred embodiment, R⁵ is —(C₁-C₁₂)-alkyl. Preferably R⁵ isselected from methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl,sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2-dimethylpropyl.More preferably R⁵ is selected from methyl and ethyl. Most preferably R⁵is methyl.

In one preferred embodiment, R⁶ and R⁷ are each independently selectedfrom —H, —(C₁C₁₂)-alkyl and —(C₆-C₂₀)-aryl. Preferably R⁶ and R⁷ areeach independently selected from —H, methyl, ethyl, n-propyl, 2-propyl,n-butyl, 2-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl,2-methylbutyl, 3-methylbuty , 3-methylbut-2-yl, 2-methylbut-2-yl,2,2-dimethylpropyl and phenyl.

More preferably R⁶ and R⁷ are each independently selected from —H,methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, sec-butyl,tert-butyl and phenyl.

Preferably not more than one of the radicals R⁶ and R⁷ is —H.

In one embodiment, R⁵ is methyl and R⁶ and R⁷ are selected independentlyfrom —H, methyl, tert-butyl and phenyl, with not more than one of theradicals R⁶ and R⁷ being —H.

In an alternative embodiment, R⁶ and R⁷ are each independently selectedfrom —(C₁-C₁₂)-alkyl and —(C₆-C₂₀)-aryl. Preferably R⁶ and R⁷ in thiscase are each independently selected from methyl, ethyl, n-propyl,2-propyl, n-butyl, 2-butyl, sec-butyl, tent-butyl, n-pentyl, 2-pentyl,3-pentyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl,2-methylbut-2-yl, 2,2-dimethylpropyl and phenyl.

More preferably R⁶ and R⁷ in this case are each independently selectedfrom methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, sec-butyl,tent-butyl and phenyl, In this embodiment, in particular, R⁵ may bemethyl, and R⁶ and R⁷ are each independently selected from methyl,tert-butyl and phenyl.

In one preferred embodiment, the first alcohol is selected fromtert-butanol, 3,3-dimethyl-butan-2-ol and 1-phenylethanol.

The alkoxycarbonylation according to the invention is catalysed by a Pdcomplex. The Pd complex may either be added in process step b) as apreformed complex comprising Pd and the phosphine ligands or be formedin situ from a compound comprising Pd and the free phosphine ligand. Inthis context, the compound comprising Pd is also referred to as catalystprecursor.

The preformed complexes may also comprise further ligands whichcoordinate to the metal atom. These are, for example, ethylenicallyunsaturated compounds or anions. Suitable additional ligands are, forexample, styrene, acetate anions, maleimides (e.g. N-methyl-maleimide),1,4-naphthoquinone, trifluoroacetate anions or chloride anions.

In the case that the catalyst is formed in situ, the ligand can be addedin excess, such that the unbound ligand is also present in the reactionmixture.

In the case of the complex which is added right at the start as well, itis additionally possible to add further ligand, such that unbound ligandis also present in the reaction mixture.

In one variant, the compound comprising Pd is selected from palladiumchloride (PdCl₂), palladium(II) acetylacetonate [Pd(acac)₂],palladium(II) acetate [Pd(OAc)₂], dichloro(1,5-cyclooctadiene)palladium(II) [Pd(cod)₂Cl₂], bis(dibenzylideneacetone)palladium[Pd(dba)₂], bis(acetonitrile)dichloropalladium(II) [Pd(CH₃CN)₂Cl₂],palladium(cinnamyl) dichloride [Pd(cinnamyl)Cl₂].

Preferably, the compound comprising Pd is PdCl₂, Pd(acac)₂ or Pd(OAc)₂.Pd(acac)₂ is particularly suitable.

The second alcohol in process step c) may be branched or linear, cyclic,alicyclic or partly cyclic, and is especially a C₁—to C₃₀-alkanol, It ispossible to use monoalcohols or polyalcohols.

Preferably, the alcohol used in step c) is a primary alcohol,

The alcohol used is preferably an aliphatic alcohol. An aliphaticalcohol in the context of this invention refers to an alcohol which doesnot comprise any aromatic groups, i.e., for example, an alkanol, alkenolor alkynol. Therefore, unsaturated nonaromatic alcohols are alsopermitted.

The alcohol in process step c) comprises preferably 1 to 30 carbonatoms, more preferably 1 to 22 carbon atoms, especially preferably 1 to12 carbon atoms. It may be a monoalcohol or a polyalcohol.

The alcohol may, in addition to the one or more hydroxyl groups, containfurther functional groups. Preferably, the alcohol may additionallycomprise one or more functional groups selected from carboxyl,thiocarboxyl, sulpho, sulphinyl, carboxylic anhydride, imide, carboxylicester, sulphonic ester, carbamoyl, sulphamoyl, cyano, carbonyl,carbonothioyl, sulphhydryl, amino, ether, thioether, or silyl groupsand/or halogen substituents.

In one embodiment, the alcohol does not comprise any further functionalgroups except for hydroxyl groups.

In one variant of the process, the alcohol in process step c) isselected from the group of the monoalcohols.

In one variant of the process, the alcohol in process step c) isselected from: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol,2-butanol, sec-butanol, tert-butanol, 1-pentanol, 2-pentanol,3-pentanol, 1-hexanol, cyclohexanol, 2-ethylhexanol, isononanol,2-propyl-heptanol, phenol, benzyl alcohol.

In a preferred variant, the alcohol in process step c) is selected frommethanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol,2-propanol, tert-butanol, 3-pentanol, cyclohexanol, and mixturesthereof.

In one variant of the process, the alcohol in process step c) isselected from the group of the polyalcohols.

In one variant of the process, the alcohol in process step c) isselected from: dials, trials, tetraols.

In one variant of the process, the alcohol in process step c) isselected from: cyclohexane-1,2-dial, ethane-1,2-diol, propane-1,3-diol,glycerol, butane-1,2,4-triol, 2-hydroxymethylpropane- 1,3-diol,1,2,6-trihydroxyhexane, pentaerythritol,1,1,1-tri(hydroxyrnethyl)ethane, catechol, resorcinol andhydroxyhydroquinone.

In one variant of the process, the alcohol in process step c) isselected from: sucrose, fructose, mannose, sorbose, galactose andglucose.

In a preferred embodiment of the process, the alcohol in process step c)is selected from methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol,1-hexanol.

In a particularly preferred variant of the process, the alcohol inprocess step c) is selected from methanol and ethanol.

In a particularly preferred variant of the process, the alcohol inprocess step c) is methanol

In one variant of the process, the alcohol in process step c) is used inexcess.

In one variant of the process, the alcohol in process step c) is usedsimultaneously as solvent.

In one variant of the process, a further solvent is used, selected from:toluene, xylene, tetrahydrofuran (THF) and methylene chloride (CH₂Cl₂).

CO is fed in in step d) preferably at a partial CO pressure between 0.1and 10 MPa (1 to 100 bar), preferably between 1 and 8 MPa (10 to 80bar), more preferably between 2 and 4 MPa (20 to 40 bar).

The reaction mixture is heated in step e) of the process according tothe invention preferably to a temperature between 10° C. and 180° C.,preferably between 20 and 160° C., more preferably between 40 and 120°C., in order to convert the alcohol to an ester.

The molar ratio of the alcohol initially charged in step a) to thealcohol added in step c) is preferably between 1:1 and 1:20, morepreferably 1:2 to 1:10, more preferably 1:3 to 1:4.

The mass ratio of Pd to the alcohol initially charged in step a) ispreferably between 0.001% and 0.5% by weight, preferably between 0,01%and 0.1% by weight, more preferably between 0.01% and 0.05% by weight.

The molar ratio of the phosphine ligand to Pd is preferably between0.1:1 and 400:1, preferably between 0.5:1 and 400:1, more preferablybetween 1:1 and 100:1, most preferably between 2:1 and 50:1.

Preferably, the process is conducted with addition of an acid. In onevariant, the process therefore additionally comprises step c′): addingan acid to the reaction mixture. This may preferably be a Brøonsted orLewis acid.

Suitable Brøensted acids preferably have an acid strength of pK_(a)≦5,preferably an acid strength of pK_(a)≦3. The reported acid strengthpK_(a) is based on the pK_(a) determined under standard conditions (25°C., 1.01325 bar). In the case of a polyprotic acid, the acid strengthpK_(a) in the context of this invention relates to the pK_(a) of thefirst protolysis step.

Preferably, the acid is not a carboxylic acid.

Suitable Brønsted acids are, for example, perchloric acid, sulphuricacid, phosphoric acid, methylphosphonic acid and sulphonic acids.Preferably, the acid is sulphuric acid or a sulphonic acid. Suitablesulphonic acids are, for example, methanesulphonic acid,trifluoromethanesulphonic acid, tert-butanesulphonic acid,p-toluenesulphonic acid (PTSA), 2-hydroxypropane-2-sulphonic acid,2,4,6-trimethylbenzenesulphonic acid and dodecylsulphonic acid.Particularly preferred acids are sulphuric acid, methanesulphonic acid,trifluoromethanesulphonic acid and p-toluenesulphonic acid.

A Lewis acid used may, for example, be aluminium triflate

In one embodiment, the amount of acid added in step c′) is 0,3 to 40 mol%, preferably 0.4 to 15 mol %, more preferably 0.5 to 5 mol %, mostpreferably 0.6 to 4 mol %, based on the molar amount of the alcohol usedin step a).

It is also possible for a molecular sieve to be added to the reactionmixture. In certain cases, this measure increases the yield of ester.Suitable for this purpose, for example, are molecular sieves comprisingzeolite or comprising carbon, preferably molecular sieves comprisingzeolite. The pore size of the molecular sieve is preferably in the rangefrom 1 to 10 Å, more preferably in the range from 2 to 6 Å, mostpreferably in the range from 3 to 5 Å.

EXAMPLES

The examples which follow illustrate the invention.

General Procedures

All the preparations which follow were carried out under protective gasusing standard Schlenk techniques, The solvents were dried over suitabledesiccants before use (Purification of Laboratory Chemicals, W. L. F.Armarego (Author), Christina Chai (Author). Butterworth Heinemann(Elsevier), 6th edition, Oxford 2009).

Phosphorus trichloride (Aldrich) was distilled under argon before use.All preparative operations were effected in baked-out vessels. Theproducts were characterized by means of NMR spectroscopy. Chemicalshifts (δ) are reported in ppm. The ³¹P NMR signals were referenced asfollows: SR_(31p)═SR_(1H)*(BF_(31p)/BF_(1H)) ═SR_(1H)*0.4048. (Robin K.Harris, Edwin D. Becker, Sonia M. Cabral de Menezes, Robin Goodfellow,and Pierre Granger, Pure Appl. Chem., 2001, 73, 1795-1818; Robin K.Harris, Edwin D. Becker, Sonia M. Cabral de Menezes, Pierre Granger, RoyE. Hoffman and Kurt W. Zilm, Pure Appl. Chem., 2008, 80, 59-84).

The recording of nuclear resonance spectra was effected on Bruker Avance300 or Bruker Avance 400, gas chromatography analysis on Agilent GC7890A, elemental analysis on Leco TruSpec CHNS and Varian ICP-OES 715,and ESI-TOF mass spectrometry on Thermo Electron Finnigan MAT 95-XP andAgilent 6890 N/5973 instruments.

Preparation of chloro-2-pyridyl-tert-butylphosphine (Precursor A)

The Grignard for the synthesis of chloro-2-pyridyl-t-butylphosphine isprepared by the “Knochel method” with isopropylmagnesiurn chloride(Angew. Chem. 2004, 43, 2222-2226). The workup is effected according tothe method of Budzelaar (Organometallics 1990, 9, 1222-1227).

8.07 ml of a 1.3 M isopropylmagnesium chloride solution (Knochel'sreagent) are introduced into a 50 ml round-bottom flask with magneticstirrer and septum, and cooled to −15° C.

Thereafter, 953.5 μl (10 mmol) of 2-bromopyridine are rapidly addeddropwise. The solution immediately turns yellow. It is allowed to warmup to −10° C. The conversion of the reaction is determined as follows:about 100 μl solution are taken and introduced into 1 ml of a saturatedammonium chloride solution. If the solution “bubbles”, not much Grignardhas formed yet. The aqueous solution is extracted with a pipette ofether and the organic phase is dried over Na₂SO₄. A GC of the etherealsolution is recorded. When a large amount of pyridine has formedcompared to 2-bromopyridine, conversions are high. At −10° C., there hasbeen little conversion. After warming up to room temperature andstirring for 1-2 hours, the reaction solution turns brown-yellow. A GCtest shows complete conversion, Now the Grignard solution can be slowlyadded dropwise with a syringe pump to a solution of 1.748 g (11 mmol) ofdichloro.tert-butylphosphine in 10 ml of THF which has been cooled to−15° C. beforehand. It is important that thedichloro-tert-butylphosphine solution is cooled. At room temperature,considerable amounts of dipyridyl-tert-butylphosphine would be obtained.A clear yellow solution is initially formed, which then turns cloudy.The mixture is left to warm up to room temperature and to stirovernight, According to GC-MS, a large amount of product has formed. Thesolvent is removed under high vacuum and a whitish solid which is brownin places is obtained. The solid is suspended with 20 ml of heptane andthe solid is comminuted in an ultrasound bath. After allowing the whitesolid to settle out, the solution is decanted. The operation is repeatedtwice with 10-20 ml each time of heptane, After concentration of theheptane solution under high vacuum, it is distilled under reducedpressure. At 4.6 mbar, oil bath 120° C. and distillation temperature 98°C., the product can be distilled. 1.08 g of a colourless oil areobtained. (50%).

Analytical data: ¹H NMR (300 MHz, C₆D₆): δ 8.36 (m, 1H, Py), 7.67 (m,1H, Py), 7.03-6.93(m, 1H, Py), 6.55-6.46 (m, 1H, Py), 1.07 (d, J=13.3Hz, 9H, t-Bu).

¹³C NMR (75 MHz, C₆D₆): δ 162.9, 162.6, 148.8, 135.5, 125.8, 125.7,122.8, 35.3, 34.8, 25.9 and 25.8.

³¹P NMR (121 MHz, C₆D₆) δ 6 97.9,

MS (El) m:z (relative intensity) 201 (M⁺, 2), 147(32), 145 (100), 109(17), 78 (8), 57.1 (17).

Preparation of Ligand 1 (α,α′-bis(2-pyridyl(t-butyl)phosphino)o-xylene)

675 mg (27.8 mmol, 4 eq) of Mg powder are weighed out in a glovebox in a250 ml round-bottom flask with a nitrogen tap and magnetic stirrer bar,and the flask is sealed with a septum. High vacuum is applied to theround-bottom flask (about 5×10⁻² mbar) and it is heated to 90° C. for 45minutes. After cooling down to room temperature, 2 grains of iodine areadded and the mixture is dissolved in 20 ml of THF. The suspension isstirred for about 10 minutes until the yellow colour of the iodine hasdisappeared. After the magnesium powder has settled out, the cloudy THFsolution is decanted and the activated magnesium powder is washed twicewith 1-2 ml of THF. Then another 20 ml of fresh THE are added. At roomtemperature, a solution of 1.21 g (6.9 mmol) of α,α′-dichloro-o-xylenein 70 ml of THF is slowly added dropwise with a syringe pump. The THFsolution gradually turns a darker colour. The next day, the THFsuspension is filtered to remove the unconverted magnesium powder andthe content of Grignard compound is determined as follows:

1 ml of Grignard solution is quenched in a saturated aqueous solution ofNH₄Cl and extracted with ether. After drying over Na₂SO₄, a GC of theether solution is recorded. In qualitative terms, it is observed thatexclusively o-xylene has formed,

Quantitative determination of the content of the Grignard solution:

1 ml of Grignard solution is quenched with 2 ml of 0,1 M HCl and theexcess acid is titrated with 0.1 M NaOH. A suitable indicator is anaqueous 0,04% brornocresol solution. The colour change goes from yellowto blue. 0.74 ml of 0.1 M NaOH has been consumed. 2 ml-0.74 ml =1.26 ml,corresponding to 0.126 mmol of Grignard compound, Since a di-Grignard ispresent, the Grignard solution is 0.063 M. This is a yield exceeding90%.

In a 250 ml three-neck flask with reflux condenser and magnetic stirrer,under argon, 1.8 g (8.66 mmol) of chlorophosphine (2-Py(tBu)PCI) aredissolved in 10 ml of THF and cooled to −60° C. Then 55 ml of theabove-stipulated Grignard solution (0.063 M, 3.46 mmol) are slowly addeddropwise at this temperature with a syringe pump. The solution at firstremains clear and then turns intense yellow. After 1.5 hours, thesolution turns cloudy. The mixture is left to warm up to roomtemperature overnight and a clear yellow solution is obtained. Tocomplete the reaction, the mixture is heated under reflux for 1 hour.After cooling, 1 ml of H₂O is added and the solution loses colour andturns milky white. After removing THF under high vacuum, a stringy, paleyellow solid is obtained. 10 ml of water and 10 ml of ether are addedthereto, and two homogeneous clear phases are obtained, which have goodseparability. The aqueous phase is extracted twice with ether. After theorganic phase has been dried with Na₂SO₄, the ether is removed underhigh vacuum and a stringy, almost colourless solid is obtained. Thelatter is dissolved in 5 ml of MeOH while heating on a water bath andfiltered through Celite. At −28° C., 772 mg of product are obtained inthe form of white crystals overnight. (51%), After concentration, it waspossible to isolate another 100 mg from the mother solution. The overallyield is 57.6%.

¹H NMR (300 MHz, C₆D₆): δ 8.58 (m, 2H, Py), 7.31-7.30 (m, 2H, benzene),7.30-7.22 (m, 2H, Py), 6.85-6.77 (m, 2H, Py), 6.73 (m, 2H, benzene),6.57-6.50 (m, 2H, py), 4.33 (dd, J=13.3 and 4.3 Hz, 2H, CH₂), 3.72-3.62(m, 2H, CH₂), 121(d, J=11.8 Hz, 18H, tBu),

¹³C NMR (75 MHz, C₆D₆): δ 161.3, 161.1, 149.6, 137.8, 137.7, 134.5,133.3, 132.7, 131.4, 131.3, 125.7, 122.9, 30.7, 30.5, 28.2, 28.0, 26,5,26.4, 26.2, and 26.1.

³¹P NMR (121 MHz, C₆D₆) δ 8.8, EA calculated for C₂₆H₃₄N₂P₂; C, 71,54:H, 7.85; N, 6.56; P,14.35, found: C, 71.21; H, 7.55; N, 6.56; P, 14.35.

Comparative Ligand

The comparative ligand used in the following examples is1,2-bis(di-tert-butylphosphino-methyl)benzene (DTBMB, ligand 3).

Methoxycarbonylation of tert-butanol

1) Without Ligand (Comparative Example)

A 4 ml glass reaction vessel (vial) is charged under argon withPd(acac)₂ (3.1 mg, 0.5 mol %), PTSA (28.5 mg, 7.5 mol %) and a magneticstirrer. Then, under argon, MeOH (2 ml) and tert-butanol (0.2 ml, 2mmol) are added. This vial is placed in a metal plate fabricated forthis purpose, and the plate with vial is transferred to a 300 mlautoclave from Parr Instruments. The autoclave is purged three timeswith CO and then charged with 50 bar of CO at room temperature. Thereaction is carried out with magnetic stirring at 120° C. for 20 hours.After cooling down to room temperature, the autoclave is cautiouslydecompressed. The yield was carried out by means of GC analysis withisooctane (200 pi) as internal standard (0% yield of methyl3-methylbutanoate).

2) Ligand 3 (Comparative Example)

A 4 ml glass reaction vessel (vial) is charged under argon withPd(acac)₂ (3.1 mg, 0,5 mol %), 3 (15.8 mg, 2 mol %), PTSA (28.5 mg, 7.5mol %) and a magnetic stirrer. Then, under argon, MeOH (2 ml) andtent-butanol (0.2 ml, 2 mmol) are added. This vial is placed in a metalplate fabricated for this purpose, and the plate with vial istransferred to a 300 ml autoclave from Parr Instruments. The autoclaveis purged three times with CO and then charged with 50 bar of CO at roomtemperature. The reaction is carried out with magnetic stirring at 120°C. for 20 hours, After cooling down to room temperature, the autoclaveis cautiously decompressed. The yield was carried out by means of GCanalysis with isooctane (200 μl) as internal standard (0% yield ofmethyl 3-methylbutanoate).

3) Ligand 1

A 4 ml glass reaction vessel (vial) is charged under argon withPd(acac)₂ (3.1 mg, 0.5 mol %), 1 (17,5 mg. 2 mol %), PTSA (28.5 mg. 7.5mol %) and a magnetic stirrer. Then, under argon, MeOH (2 ml) andtert-butanol (0.2 ml, 2 mmol) are added. This vial is placed in a metalplate fabricated for this purpose, and the plate with vial istransferred to a 300 ml autoclave from Parr Instruments. The autoclaveis purged three times with CO and then charged with 50 bar of CO at roomtemperature. The reaction is carried out with magnetic stirring at 120°C. for 20 hours, After cooling down to room temperature, the autoclaveis cautiously decompressed. The yield was carried out by means of GCanalysis with isooctane (200 μl) as internal standard (99% yield ofmethyl 3-rnethylbutanoate).

The results are summarized in the following table:

Example Ligand Yield of methyl 3-methylbutanoate (%) 1 (CE) none 0 2* 30 3 (CE) 1 99 CE: comparative example *inventive example

Methoxycarbonylation of 1-phonylethanal

A 4 ml glass reaction vessel (vial) is charged under argon withPd(acac)₂ (3,1 mg, 0.5 mol %), PTSA (28.5 mg, 7 mol %), ligand 1 (8.7mg, 1 mol %) and a magnetic stirrer. Then, under argon, MeOH (2 ml) and2 mmol of 1-phenylethanol are added. This vial is placed in a metalplate fabricated for this purpose, and the plate with vial istransferred to a 300 ml autoclave from Parr instruments. The autoclaveis purged three times with CO and then charged with 50 bar of CO at roomtemperature. The reaction is carried out with magnetic stirring at 120°C. for 20 hours. After cooling down to room temperature, the autoclaveis cautiously decompressed. The product obtained was a mixture of methyl3-phenylpropanoate (n product) and methyl 2-phenylpropanoate (isoproduct). The yield was carried out by means of GC analysis withisooctane (200 μl) as internal standard (40% overall yield, n/iso ratio70/30).

Methoxycarbonylation of 3,3-dimethylbutan-2-ol

Example 1 Ligand 3

A 4 ml glass reaction vessel (vial) is charged under argon withPd(acac)₂ (3.1 mg, 0.5 mol %), 3 (15.8 mg, 2 mol %), CF₃SO₂OH (48.0 mg,16 mol %) and a magnetic stirrer. Then, under argon, toluene (2 ml) and3,3-dimethylbutan-2-ol (0.25 ml, 2 mmol) are added. This vial is placedin a metal plate fabricated for this purpose, and the plate with vial istransferred to a 300 ml autoclave from Parr Instruments. The autoclaveis purged three limes with CO and then charged with 50 bar of CO at roomtemperature. The reaction is carried out with magnetic stirring at 120°C. for 20 hours, After cooling down to room temperature, the autoclaveis cautiously decompressed. The yield was carried out by means of GCanalysis with isooctane (200 μl) as internal standard (0% yield).

Example 2 Ligand 3 with 4 Å Molecular Sieve

A 4 ml glass reaction vessel (vial) is charged under argon withPd(acac)₂ (3.1 mg, 0.5 mol %), 3 (15.8 mg, 2 mol %), CF₃SO₂OH (48.0 mg,16 mol %), 4 Å zeolite molecular sieve (4 Å MS, 20 mg) and a magneticstirrer. Then, under argon, toluene (2 ml) and 3,3-dimethylbutan-2-ol(0.25 ml, 2 mmol) are added. This vial is placed in a metal platefabricated for this purpose, and the plate with vial is transferred to a300 ml autoclave from Parr Instruments. The autoclave is purged threetimes with CO and then charged with 50 bar of CO at room temperature.The reaction is carried out with magnetic stirring at 120° C. for 20hours. After cooling down to room temperature, the autoclave iscautiously decompressed. The yield was carried out by means of GCanalysis with isooctane (200 μl) as internal standard (0% yield).

Example 3 Ligand 1

A 4 ml glass reaction vessel (vial) is charged under argon withPd(acac)₂ (3.1 mg, 0.5 mol %), 1 (17.5 mg, 2 mol %), CF₃SO₂OH (48.0 mg,16 mol %) and a magnetic stirrer. Then, under argon, toluene (2 ml) and3,3-dimethylbutan-2-ol (0.25 ml, 2 mmol) are added. This vial is placedin a metal plate fabricated for this purpose, and the plate with vial istransferred to a 300 ml autoclave from Parr Instruments. The autoclaveis purged three times with CO and then charged with 50 bar of CO at roomtemperature. The reaction is carried out with magnetic stirring at 120°C. for 20 hours. After cooling down to room temperature, the autoclaveis cautiously decompressed. The yield was carried out by means of GCanalysis with isooctane (200 μl) as internal standard (10% yield).

Example 4 Ligand 1 with 4 Å Molecular Sieve

A 4 ml glass reaction vessel (vial) is charged under argon withPd(acac)₂ (3.1 mg, 0.5 mol %), 1 (17.5 mg, 2 mol %), CF₃SO₂OH (48.0 mg,16 mol %), 4 Å MS (20 mg) and a magnetic stirrer. Then, under argon,toluene (2 ml) and 3,3-dimethylbutan-2-ol (0.25 ml, 2 mmol) are added.This vial is placed in a metal plate fabricated for this purpose, andthe plate with vial is transferred to a 300 ml autoclave from ParrInstruments. The autoclave is purged three times with CO and thencharged with 50 bar of CO at room temperature. The reaction is carriedout with magnetic stirring at 120° C. for 20 hours. After cooling downto room temperature, the autoclave is cautiously decompressed. The yieldwas carried out by means of GC analysis with isooctane (200 μl) asinternal standard (20% yield).

The results are summarized in the following table:

Example Ligand Additive Yield n/iso ratio 1 (CE) 3 0% — 2 (CE) 3 4 Å MS0% — 3* 1 10% 75/25 4* 1 4 Å MS 20% 74/26 CE: comparative examples*inventive examples

The above experiments show that by means of the process of theinvention, using the ligands according to the invention, a series ofstructurally different alcohols can be reacted as substrate in analkoxycarbonylation reaction with CO and a further alcohol to formesters, Conversely, the ligand known from the prior art is not suitablefor the reaction of alcohols in an alkoxycarbonylation reaction.

1. Process comprising the following process steps: a) introducing afirst alcohol, the first alcohol having 2 to 30 carbon atoms; b) addinga phosphine ligand and a compound which comprises Pd, or adding acomplex comprising Pd and a phosphine ligand; c) adding a secondalcohol; d) supplying CO; e) heating the reaction mixture, the firstalcohol reacting with CO and the second alcohol to form an ester; wherethe phosphine ligand is a compound of formula (I)

where m and n are each independently 0 or 1; R′, R², R³, R⁴ are eachindependently selected from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₃-C₁₂)-heterocycloalkyl, —(C₆ C₂₀)-aryl, —(C₃-C₂₀)-heteroaryl; atleast one of the R¹, R², R³, R⁴ radicals is a —(C₃-C₂₀)-heteroarylradical; and R¹, R², R³, R⁴, if they are —(C₁-C₁₂)-alkyl,—(C₃-C₁₂)-cycloalkyl,—(C₃-C₁₂)-heterocycloalkyl, —(C₆-C₂₀)-aryl or—(C₃-C₂₀)-heteroaryl, may each independently be substituted by one ormore substituents selected from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₃-C₁₂)-heterocycloalkyl, —O—(C₁-C₁₂)-alkyl,—O—(C₁-C₁₂)-alkyl-(C₆-C₂₀)-aryl, —O—(C₃-C1₂)-cycloalkyl,—S—(C₁-C₁₂)-alkyl, —S—(C₃-C₁₂)-cycloalkyl, —COO—(C₁-C₁₂)-alkyl,—COO—(C₃-C₁₂)-cycloalkyl, —CONH—(C₁-C₁₂)-alkyl,—CONH—(C₃-C₁₂)-cycloalkyl, —CO—(C₁-C₁₂)-alkyl, —CO—(C₃-C₁₂)-cycloalkyl,—N—[(C₁-C₁₂)-alkyl]₂, —(C₆-C₂₀)-aryl, —(C₆-C₂₀)-aryl-(C₁-C₁₂)-alkyl,—(C₆-C₂₀)-aryl-O—(C₁-C₁₂)-alkyl, —(C₃-C₂₀)-heteroaryl,—(C₃-C₂₀)-heteroaryl-(C₁-C₁₂)-alkyl,—(C₃-C₂₀)-heteroaryl-O—(C₁-C₁₂)-alkyl, —COON, —OH, —SO₃H, —NH₂, halogen.2. Process according to claim 1, where the phosphine ligand is acompound of one of the formulae (II) and (Ill)


3. Process according to claim 1, where at least two of the R¹, R², R³,R⁴ radicals are a —(C₃-C₂₀)-heteroaryl radical.
 4. Process according toclaim 1, where the R¹ and R³ radicals are each a —(C₃-C₂₀)-heteroarylradical,
 5. Process according to claim 1, where the R¹ and R³ radicalsare each a —(C₃-C₂₀)-heteroaryl radical; and R² and R⁴ are eachindependently selected from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₃-C₁₂)-heterocycloalkyl, —(C₆-C₂₀)-aryl.
 6. Process according toclaim 1, where the R¹ and R³ radicals are each a —(C₃-C₂₀)-heteroarylradical; and R² and R⁴ are each independently selected from—(C₁-C₁₂)-alkyl.
 7. Process according to claim 1, where R¹, R², R³, R⁴,if they are a heteroaryl radical, are each independently selected fromfuryl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, furazanyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidyl, pyrazinyl, benzofuranyl, indolyl, isoindolyl, benzimidazolyl,quinolyl, isoquinolyl.
 8. Process according to claim 1, where thephosphine ligand is a compound of formula (1)


9. Process according to claims 1, wherein the first alcohol in processstep a) is a compound of formula (IV)

where R⁵ is selected from —(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl,—(C₆-C₂₀)-aryl; and R⁶ and R⁷ are each independently selected from —H,—(C₁-C₁₂)-alkyl, —(C₃-C₁₂)-cycloalkyl, —(C₆-C₂₀)-aryl.
 10. Processaccording to claim 9, wherein R⁵ is —(C₁-C₁₂)-alkyl.
 11. Processaccording to claim 9, where R⁶ and R⁷ are each independently selectedfrom —H, —(C₁-C₁₂ )-alkyl, —(C₆-C₂₀)-aryl,
 12. Process according toclaim 9, wherein not more than one of the radicals R⁶ and R⁷ is —H. 13.Process according to claim 1, wherein the compound comprising Pd inprocess step b) is selected from palladium dichloride, palladium(II)acetylacetonate, palladium(II) acetate, dichloro(1,5-cyclooctadiene)palladium(II), bis(dibenzylideneacetone)palladium,bis(acetonitrile)dichloropalladium(II), palladium(cinnamyl) dichloride.14. Process according to claim 1, wherein the second alcohol in processstep c) is selected from methanol, ethanol, 1-propanol, 1-butanol,1-pentanol, 1-hexanol, 2-propanol, tent-butanol, 3-pentanol,cyclohexanol, and mixtures thereof.
 15. Process according to claim 1,wherein the first alcohol in process step a) is a secondary or tertiaryalcohol and the second alcohol in process step c) is a primary alcohol.